US10981908B2 - Aryl hydrocarbon receptor (AHR) modulator compounds - Google Patents

Aryl hydrocarbon receptor (AHR) modulator compounds Download PDF

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US10981908B2
US10981908B2 US16/479,130 US201816479130A US10981908B2 US 10981908 B2 US10981908 B2 US 10981908B2 US 201816479130 A US201816479130 A US 201816479130A US 10981908 B2 US10981908 B2 US 10981908B2
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alkyl
int
pyrrolo
methyl
independently selected
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US20190389857A1 (en
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Christoph Steeneck
Ulrich Deuschle
Michael Albers
Thomas Hoffmann
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Fuics Development Ltd
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Phenex Pharmaceuticals AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to compounds which can act as aryl hydrocarbon receptor (AhR) modulators and, in particular, as AhR antagonists.
  • the invention further relates to the use of the compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said aryl hydrocarbon receptor by said compounds.
  • the aryl hydrocarbon receptor is a ligand-modulated transcription factor, belonging to the basic helix-loop-helix PAS (Per-Amt-Sim homology domain) family, that is expressed in most tissues in mice and humans and known to mediate many of the toxicities of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in mice.
  • the AhR protein is localized in the cytoplasm of eukaryotic cells in complexes with HSP90 and other proteins. Binding of agonistic ligands, such as TCDD, leads to dissociation of AhR from the HSP90 containing complex, transport to the nucleus and association with its heterodimeric partner ARNT.
  • This heterodimeric complex can bind to AhR response elements located in promoter regions of genes such as CYP1A1, CYP1B1, ALDH3A1, NQO1, UGT1A1 etc. and induces the transcription of such genes in case of very potent and efficacious AhR agonists, such as TCDD.
  • CYP1A1 By regulating the expression of genes involved in xenobiotic transformation (e.g. CYP1A1), the AhR plays a significant role in the detoxification of xenobiotic substances in liver and intestine, which are prominent locations of AhR expression. This activity might be underlying some of the described chemoprevention and tumor suppression effects exerted by AhR.
  • CYP1A1 is known to metabolize some pro-cancerogens, such as benzo(a)pyrene into DNA reactive intermediates leading to mutagenesis and tumor formation (Murray et al. Nat Rev Cancer. 2014 December; 14(12):801-14; Safe et al Toxicol Sci. 2013 September; 135(1):1-16).
  • the AhR is relatively strongly expressed in intestinal epithelial tissues, lung epithelium and skin. In these tissues the AhR expression is particularly high in cells of lymphoid origin such as T-cells, Dendritic Cells, Langerhans Cells, Macrophages, Mast cells etc.
  • One possible function in these compartments is to integrate signals from the commensal microbiomes in the intestine, the lung and the skin, which are known to produce diverse mixtures of indolic AhR modulators that are thought to balance the responses of the immune system towards the microbiome (Bessede et al., Nature. 2014 Jul. 10; 511(7508):184-90, Zelante et al. Immunity. 2013 Aug. 22; 39(2):372-85, Romani et al., Eur J Immunol. 2014 November; 44(11):3192-200).
  • AhR AhR ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • AhR modulators and in particular modulators with primarily antagonistic activities might be useful as medicaments for the treatment of solid tumors (e.g., pancreatic cancer, prostate cancer, breast cancer, colon cancer).
  • solid tumors e.g., pancreatic cancer, prostate cancer, breast cancer, colon cancer.
  • the problem underlying the present invention is to provide compounds which have a AhR-antagonistic activity and can be used in the treatment and/or prophylaxis of AhR-mediated diseases.
  • a and B are independently selected from 6- to 10-membered mono- or bicyclic aryl and 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein aryl and heteroaryl are unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, CN, C 1-6 -alkyl, O—C 1-6 -alkyl, C(O)OR a , OC(O)R a , S(O)—C 1-6 -alkyl, S(O) 2 —C 1-6 -alkyl, N(R a ) 2 , C(O)N(R a ) 2 , NR a C(O)—C 1-6 -alkyl, S(O) 2 N(R a ) 2 , NR a S(O) 2 —C 1-3 -alkyl and C 1-3 -cycloal
  • R b in the compound according to Formula (I) is hydrogen.
  • a in the compound according to Formula (I) is substituted with 1 to 5 substituents selected from halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, CN, SO 2 CH 3 , C(O)OR a , C(O)N(R a ) 2 and C 3-6 -cycloalkyl which is unsubstituted or substituted with C 1-3 -alkyl or halo-C 1-3 -alkyl.
  • R 4 is independently halogen, OH, CN, C 1-6 -alkyl, O—C 1-6 -alkyl, C(O)OR a , OC(O)R a , S(O)—C 1-6 -alkyl, S(O) 2 —C 1-6 -alkyl, N(R a ) 2 , C(O)N(R a ) 2 , NR a C(O)—C 1-6 -alkyl, S(O) 2 N(R a ) 2 , NR a S(O) 2 —C 1-6 -alkyl and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, OH, CN and oxo; and n is 0 to
  • n is 1 to 5 and R 4 is independently selected from halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, CN and C 3-6 -cycloalkyl which is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C 1-3 -alkyl and halo-C 1-3 -alkyl.
  • R 4 is independently halogen, OH, CN, C 1-6 -alkyl, O—C 1-6 -alkyl, C(O)OR a , OC(O)R a , S(O)—C 1-6 -alkyl, S(O) 2 —C 1-6 -alkyl, N(R a ) 2 , C(O)N(R a ) 2 , NR a C(O)—C 1-6 -alkyl, S(O) 2 N(R a ) 2 , NR a S(O) 2 —C 1-6 -alkyl and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, OH, CN and oxo; R a is hydrogen or C
  • X is halogen, C 1-6 -alkyl or C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-3 -alkyl and halo-C 1-3 -alkyl; R 5 is independently halogen or CN; and m is 0 to 4.
  • X is CH 3 , CH 2 CH 3 , CHF 2 or CF 3 ;
  • R 5 is independently halogen or CN; and
  • m is 0 to 4.
  • B in the compound according to Formula (I) is a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, OH, CN, C 1-6 -alkyl, O—C 1-6 -alkyl, C(O)OR a , OC(O)R a , S(O)—C 1-6 -alkyl, S(O) 2 —C 1-6 -alkyl, N(R a ) 2 , C(O)N(R a ) 2 , NR a C(O)—C 1-6 -alkyl, S(O) 2 N(R a ) 2 , NR a S(O) 2 —C 1-6 -alkyl and C 3-6 -cycloalkyl, wherein the alkyl and
  • R a is hydrogen or C 1-6 -alkyl.
  • B in the compound according to Formula (I) is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl, C(O)OR a , C(O)N(R a ) 2 and C 3-6 -cycloalkyl.
  • B in the compound according to Formula (I) is a 9- or 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of C 1-6 -alkyl, halo-C 1-6 -alkyl, and C 3-6 -cycloalkyl or B is a 6- or 10-membered aryl, which is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of halogen and C 1-6 -alkyl.
  • each of R 1 , R 2 , R 3 in the compound according to Formula (I) are hydrogen.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to formula (I) and a physiologically acceptable excipient.
  • the present invention is directed to the compound according to formula (I) for use as a medicament.
  • the present invention is directed to the compound according to formula (I) or a pharmaceutical composition containing same and a physiologically acceptable excipient for use in the prophylaxis and/or treatment of a disease or condition mediated by aryl hydrocarbon receptor (AhR).
  • aryl hydrocarbon receptor AhR
  • the disease or condition mediated by aryl hydrocarbon receptor (AhR) is cancer.
  • the compound according to formula (I) is administered with one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, IDO1 inhibitor, chemotherapeutic agent, anticancer vaccine, and cytokine therapy, or wherein the compound is administered under irradiation therapy.
  • one or more therapeutic agents for cancer selected from the group consisting of PD-1 agent, PD-L1 agent, CTLA-4 agent, IDO1 inhibitor, chemotherapeutic agent, anticancer vaccine, and cytokine therapy, or wherein the compound is administered under irradiation therapy.
  • the compounds of the present invention share a common chemical structure according to formula (I) in claim 1 .
  • the present invention is directed to an enantiomer, diastereomer or pharmaceutically acceptable salt of a compound according to Formula (I).
  • a in the compound according to Formula (I) is a 6-membered aryl or a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, wherein the aryl and heteroaryl are unsubstituted or substituted with 1 to 3 substituents independently selected from OH, CN, halogen, C 1-6 -alkyl, and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen and C 1-6 -alkyl.
  • a in the compound according to Formula (I) is a 6-membered aryl substituted with 1 or 2 substituents independently selected from OH, CN, halogen, C 1-6 -alkyl, and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl may be substituted with 1 to 3 substituents independently selected from halogen and C 1-6 -alkyl.
  • a in the compound according to Formula (I) is 10-membered aryl such as a naphthalene group which is unsubstituted or substituted with 1 to 7 substituents independently selected from the group consisting of halogen, OH, CN, C 1-6 -alkyl, O—C 1-6 -alkyl, C(O)OR a , OC(O)R a , S(O)—C 1-6 -alkyl, S(O) 2 —C 1-6 -alkyl, N(R a ) 2 , C(O)N(R a ) 2 , NR a C(O)—C 1-6 -alkyl, S(O) 2 N(R a ) 2 .
  • NR a S(O) 2 —C 1-6 -alkyl and C 3-6 -cycloalkyl wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-3 -alkyl, halo-C 1-3 -alkyl, OH, CN and oxo.
  • a in the compound according to Formula (I) is a 6- or 10-membered aryl, more preferable a phenyl group, which is fused with a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6 -alkyl and halo-C 1-6 -alkyl.
  • a in the compound according to Formula (I) is a 5- or 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected form N, O and S, which is fused with a 5- to 7-membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, N and S, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6 -alkyl and halo-C 1-6 -alkyl.
  • a in the compound according to Formula (I) is a 6-membered aryl or a 5- to 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, wherein the aryl and heteroaryl are unsubstituted or substituted with 1 or 2 substituents independently selected from halogen, C 1-6 -alkyl, and halo-C 1-6 -alkyl.
  • a in the compound according to Formula (I) is a 6-membered monocyclic heteroaryl containing 1 to 3 nitrogen atoms, which is substituted with 1 or 2 substituents independently selected from OH, CN, halogen, C 1-6 -alkyl, O—C 1-6 -alkyl and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from halogen and C 1-6 -alkyl.
  • a in the compound according to Formula (I) is a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, which is substituted with 1 or 2 substituents independently selected from OH, CN, halogen, C 1-6 -alkyl, and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen and C 1-6 -alkyl.
  • X is CH 3 , CH 2 CH 3 , CHF 2 , OCF 3 , OCH 3 or CF 3 ;
  • R 5 is H, CN or halogen; and
  • m is 0 to 4.
  • B in the compound according to Formula (I) is a 5- to 10-membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 to 3 substituents independently selected from OH, CN, halogen, C 1-6 -alkyl, and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen and C 1-6 -alkyl.
  • B in the compound according to Formula (I) is a 5- to 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 to 3 substituents independently selected from OH, CN, halogen, C 1-6 -alkyl, and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen and C 1-6 -alkyl.
  • B in the compound according to Formula (I) is a 5- to 6-membered monocyclic heteroaryl which is unsubstituted or substituted with 1 to 3 substituents independently selected from OH, CN, halogen, C 1-6 -alkyl, and C 1-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen and C 1-6 -alkyl, wherein the heteroaryl has 1 to 3 heteroatoms independently selected from N, O and S, preferably N and O, and most preferably N.
  • B in the compound according to Formula (I) is a 5- to 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 to 3 substituents independently selected from OH, CN, halogen, C 1-6 -alkyl, and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen and C 1-6 -alkyl, wherein the heteroaryl has 1 to 3 N atoms, preferably 2 or 3 N atoms.
  • B in the compound according to Formula (I) is a 5-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted with 1 or 2 substituents independently selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and C 3-6 -cycloalkyl.
  • B in the compound according to Formula (I) is 9- or 10-membered bicyclic heteroaryl which is unsubstituted or substituted with 1 to 3 substituents independently selected from OH, CN, halogen, C 1-6 -alkyl, and C 3-6 -cycloalkyl, wherein the alkyl and cycloalkyl are unsubstituted or substituted with 1 to 3 substituents independently selected from halogen and C 1-6 -alkyl, wherein the heteroaryl has 1 to 3 N atoms, preferably 2 or 3 N atoms.
  • R 1 , R 2 , and R 3 in the compound according to Formula (I) are each independently selected from hydrogen, halogen, C 1-3 -alkyl, OH, and CN.
  • one of R 1 , R 2 , and R 3 in the compound according to Formula (I) is C 1-3 -alkyl, halogen, or CN, and the other two are hydrogen.
  • R 1 , R 2 , and R 3 in the compound according to Formula (I) are hydrogen.
  • C 1-6 -alkyl means a saturated alkyl chain having 1 to 6 carbon atoms which may be straight chained or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and hexyl.
  • O—C 1-6 -alkyl means that the alkyl chain is connected via an oxygen atom with the remainder of the molecule.
  • halo-C 1-10 -alkyl means that one or more hydrogen atoms in the alkyl chain are replaced by a halogen.
  • a preferred example thereof is CF 3 .
  • a C 3-6 -cycloalkyl group means a saturated or partially unsaturated mono- or bicyclic ring system comprising 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a 5-10-membered mono- or bicyclic heteroaromatic ring system (within the application also referred to as heteroaryl) containing up to 4 heteroatoms means a monocyclic heteroaromatic ring such as pyrrolyl, imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. It further means a bicyclic ring system wherein the heteroatom(s) may be present in one or both rings including the bridgehead atoms.
  • Examples thereof include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl, pyrazolo[1,5-a]pyrimidinyl and dibenzo[b,d]furanyl.
  • the nitrogen or sulphur atom of the heteroaryl system may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. If not stated otherwise, the heteroaryl system can be connected via a carbon or nitrogen atom. Examples for N-linked heterocycles are
  • heteroaryl contains 1 to 4 heteroatoms independently selected from the group consisting of N, O and S.
  • a 6-10-membered mono- or bicyclic aromatic ring system (within the application also referred to as aryl) means an aromatic carbon cycle such as phenyl or naphthyl.
  • halogen comprises the specific halogen atoms fluorine, bromine, chlorine and iodine.
  • any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 35 S, 36 Cl and 125 I.
  • isotopically labeled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the disclosure also includes “deuterated analogs” of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • deuterated analogs of compounds of Formula (I) in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule.
  • Such compounds may exhibit increased resistance to metabolism and thus be useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, e.g. a human. See, for example, Foster in Trends Pharmacol. Sci. 1984:5; 524.
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F labeled compound may be useful for PET or SPECT studies.
  • the concentration of such a heavier isotope, specifically deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • the compounds of the present invention can be in the form of a prodrug compound.
  • “Prodrug compound” means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • prodrug examples include compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated.
  • these compounds can be produced from compounds of the present invention according to well-known methods.
  • prodrug examples are compounds, wherein the carboxylate in a compound of the present invention is, for example, converted into an alkyl-, aryl-, choline-, amino, acyloxymethylester, linolenoylester.
  • Metabolites of compounds of the present invention are also within the scope of the present invention.
  • tautomerism like e.g. keto-enol tautomerism
  • the individual forms like e.g. the keto and enol form, are each within the scope of the invention as well as their mixtures in any ratio. Same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of the present invention may be obtained from stereoselective synthesis using optically pure starting materials. Another way to obtain pure enantiomers from racemic mixtures would use enantioselective crystallization with chiral counterions.
  • the compounds of the present invention can be in the form of a pharmaceutically acceptable salt or a solvate.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the present invention which contain acidic groups can be present on these groups and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts.
  • salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • the compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • solvates such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol.
  • the present invention provides pharmaceutical compositions comprising at least one compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients like a prodrug compound or other nuclear receptor modulators.
  • the compounds used in the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatine; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavouring such as cherry or orange flavour.
  • the compounds used in the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral including intravenous, intramuscular and subcutaneous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of the present invention are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds When treating or preventing AhR-mediated conditions for which compounds of Formula (I) are indicated, generally satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.1 mg to about 100 mg per kilogram of mammal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 350 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention can be prepared by a combination of methods known in the art including the procedures described in scheme 1 below.
  • the following reaction schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.
  • Scheme 1 describes one route of preparation for the compounds of the present invention.
  • a substituted or unsubstituted 6-chloro-3-iodopyridin-2-amine A-1 is converted to the corresponding bis methylsulfonamide A-2 with sulfonylchloride in the presence of triethylamine.
  • Treatment of A-2 with NaOH affords the corresponding mono methylsulfonamide A-3 which is converted to azaindole A-4 via Pd/Cu(I) catalysed coupling/cyclisation reaction with an appropriately substituted alkyne.
  • Boc-protection to intermediate A-5 followed by Buchwald amidation affords the corresponding amide A-6.
  • Intermediate A-6 is converted to compounds of structure A-7 by deprotection with for example TFA.
  • Scheme 2 describes an alternative route of preparation for the compounds of the present invention.
  • a substituted or unsubstituted 6-chloro-1H-pyrrolo[2,3-b]pyridine B-1 is converted to the corresponding 2-(trimethylsilyl)ethoxymethyl protected intermediate B-2 through treatment with NaH and ((chloromethoxy) methyl)trimethylsilane.
  • Intermediate B-2 can be iodinated by treatment with n-BuLi at ⁇ 78° C. followed by addition of iodine to give iodide B-3.
  • Suzuki coupling of B-3 with a boronic acid or ester affords intermediates of structure B-4.
  • Buchwald amidation with an amide gives intermediates of structure B-5 which can be deprotected with e.g. BF 3 .Et 2 O to afford compounds of structure B-6.
  • compounds of structure B-6 can be converted into compounds of structure B-8 in a sequence of amide hydrolysis with NaOH followed by amide coupling with a carboxylic
  • Step 1 ((3-Fluoro-2-(trifluoromethyl)phenyl)ethynyl)trimethylsilane (Int 1b)
  • Step 1 N-(6-Chloro-3-iodopyridin-2-yl)-N-(methylsulfonyl)methanesulfonamide (Int 2b)
  • Methanesulfonyl chloride (5.5 mL, 70.9 mmol) was added dropwise to a solution of 6-chloro-3-iodopyridin-2-amine (Int 2a) (5.0 g, 19.7 mmol) in pyridine (50 mL) at 0° C. The mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated to dryness and the residue was purified by column chromatography (gradient 5%-100% EtOAc in DCM) to give the title compound as a yellow solid.
  • Step 4 tert-Butyl 6-chloro-2-(o-tolyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Int 2)
  • Step 2 6-Chloro-1-methyl-2-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (Int 5)
  • Step 1 3-(6-Chloro-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)furan-2-carbaldehyde (Int 8a)
  • Step 2 6-Chloro-2-(2-(difluoromethyl)furan-3-yl)-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (Int 8b)
  • Step 4 tert-Butyl 6-chloro-2-(2-(difluoromethyl)furan-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Int 8)
  • Step 1 6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (Int 20b)
  • Step 2 6-Chloro-2-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (Int 20c)
  • Step 3 6-Chloro-2-(2-cyclopropylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (Int 20)
  • Step 2 6-Chloro-3-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (Int 22b)
  • Step 3 6-Chloro-2-(2-(difluoromethyl)phenyl)-3-fluoro-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrrolo[2,3-b]pyridine (Int 22)
  • tert-Butyl nitrite (1.69 g, 16.41 mmol) was quickly added to a solution of 5-cyclopropyl-2-(trifluoromethyl)aniline (Int 23b) (1.10 g, 5.47 mmol) in CH 3 CN (50 mL) and the mixture was stirred at rt under N 2 for 2 min.
  • CuBr 2 (3.02 g, 13.66 mmol) was added and the mixture was stirred at rt under N 2 for 3 h.
  • Water (20 mL) was added and the mixture was extracted with EtOAc (2 ⁇ 50 mL). The combined organic layers were concentrated to dryness and the residue was purified by column chromatography (0-2% DCM in PE) to give the title compound as colorless oil.
  • Step 3 ((5-Cyclopropyl-2-(trifluoromethyl)phenyl)ethynyl)trimethylsilane (Int 23d)
  • Step 4 4-Cyclopropyl-2-ethynyl-1-(trifluoromethyl)benzene (Int 23e)
  • Steps 5-6 tert-Butyl 6-chloro-2-(5-cyclopropyl-2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Int 23)
  • Step 2 ((2-(Difluoromethyl)-4,5-difluorophenyl)ethynyl)trimethylsilane (Int 24c)
  • Steps 4-5 tert-Butyl 6-chloro-2-(2-(difluoromethyl)-4,5-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Int 24)
  • NIS 6-chloro-5-methylpyridin-2-amine
  • THF THF
  • NIS 6-chloro-5-methylpyridin-2-amine
  • the mixture was then heated at 50° C. for 24 h with additional NIS (5.30 g, 23.56 mmol) being added.
  • the mixture was allowed to cool to rt and concentrated to dryness. Water (30 mL) was added and the mixture was extracted with ethyl acetate (3 ⁇ 40 mL). The combined organic layers were dried over anhydrous MgSO 4 , filtered and concentrated to dryness.
  • the residue was purified by silica gel chromatography (gradient 0-50% EtOAc in PE) to give the title compound as a white solid.
  • Step 2 1-Methyl-N-(2-(o-tolyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1H-pyrazole-5-carboxamide (1)
  • Step 1 tert-Butyl 6-(3-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-2-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2a)
  • step 1 (1a) using tert-butyl 6-chloro-2-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Int 2/1) in place of tert-butyl 6-chloro-2-(o-tolyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Int 2) and methyl 5-carbamoyl-1-methyl-1H-pyrazole-3-carboxylate (Int 3/3) in place of 1-methyl-1H-pyrazole-5-carboxamide.
  • Int 2/1 tert-butyl 6-chloro-2-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • Int 2 tert-butyl 6-chloro-2-(o-tolyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • Step 2 1-Methyl-5-((2-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)carbamoyl)-1H-pyrazole-3-carboxylic acid (2)
  • Step 1 N-(2-(2-Cyclopropylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-methyl-1H-1,2,4-triazole-5-carboxamide (4a)
  • Step 2 N-(2-(2-Cyclopropylphenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-methyl-1H-1,2,4-triazole-5-carboxamide (4)
  • Step 2 N-(2-(2-(Difluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-methyl-1H-imidazole-5-carboxamide (5)
  • Step 1 Methyl 2-(6-(1-methyl-1H-1,2,4-triazole-5-carboxamido)-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoate (6a)
  • step 1 (1a) using methyl 2-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoate (Int 6) in place of tert-butyl 6-chloro-2-(o-tolyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Int 1) and 1-methyl-1H-1,2,4-triazole-5-carboxamide (Int 3) in place of 1-methyl-1H-pyrazole-5-carboxamide.
  • Step 2 2-(6-(1-Methyl-1H-1,2,4-triazole-5-carboxamido)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoic acid (6)
  • Step 1 Methyl 1-methyl-5-((2-(2-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl) carbamoyl)-1H-pyrazole-3-carboxylate (9a)
  • Step 1 Methyl 3-(6-(1-methyl-1H-1,2,4-triazole-5-carboxamido)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)benzoate (12a)
  • Step 1 tert-Butyl 2-(2-(difluoromethyl)phenyl)-6-(N,1-dimethyl-1H-1,2,4-triazole-5-carboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (13a)
  • Step 2 N-(2-(2-(Difluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-N, 1-dimethyl-1H-1,2,4-triazole-5-carboxamide (13)
  • Step 1 N-(2-(2-(Difluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-methyl-1H-1,2,4-triazole-5-carboxamide (14a)
  • Step 2 N-(3-Bromo-2-(2-(difluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-methyl-1H-1,2,4-triazole-5-carboxamide (14b)
  • Step 3 N-(3-Cyano-2-(2-(difluoromethyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-methyl-1H-1,2,4-triazole-5-carboxamide (14c)
  • Step 4 N-(3-Cyano-2-(2-(difluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-1-methyl-1H-1,2,4-triazole-5-carboxamide (14)
  • HepG2 CYP1A1-LUC A stable cell line (HepG2 CYP1A1-LUC) was used in which part of the promoter region of the human CYP1A1 gene is stably integrated into the genome of human HepG2 hepatocytes (DSZM #ACC 180) in front of a Photinus pyralis Firefly Luciferase gene.
  • a 1210 bp fragment comprising part of the human CYP1A1 promoter was isolated via SacI and BgIII restriction digestion from Lightswitch Clone S714555 (SwitchGearGenomics) and inserted between the SacI and BgIII sites in pGL4.30 (Promega #E8481) in front of the Firefly Luciferase gene.
  • the resulting vector was linearized with NotI, transfected into HepG2 cells (DSMZ #ACC 180) and stably transfected clones selected with 250 ⁇ g/ml Hygromycin B. After repetitive rounds of subcloning and testing for robustly regulated luciferase activity after AhR agonist stimulation, a stable clonal HepG2 CYP1A1-Luc cell line was selected.
  • the HepG2 CYP1A1-Luc cells do express basal luciferase activity that can be increased via potent AhR agonists or decreased via potent AhR antagonists, added to the growth medium of the cells.

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EP4093739A1 (en) * 2020-01-23 2022-11-30 Phenex Pharmaceuticals AG Oxalamide substituted heterocyclic compounds as modulators of the aryl hydrocarbon receptor (ahr)
AU2021226411A1 (en) 2020-02-26 2022-09-22 Jaguahr Therapeutics Pte Ltd Pyridopyrimidine derivatives useful in modulation of AhR signalling
WO2021242955A1 (en) * 2020-05-28 2021-12-02 Senda Biosciences, Inc. Fused azole heterocycles as ahr antagonists
CN114181212B (zh) * 2020-09-15 2023-06-06 山东轩竹医药科技有限公司 哒嗪酮类AhR抑制剂
CN114835687B (zh) * 2021-04-02 2023-09-05 北京华森英诺生物科技有限公司 AhR抑制剂
CN115572282A (zh) * 2021-07-05 2023-01-06 华东理工大学 含芳杂环结构的吡唑酰胺类化合物及其制备方法和应用
WO2024076300A1 (en) 2022-10-03 2024-04-11 Jaguahr Therapeutics Pte Ltd Compounds useful in modulation of ahr signalling

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002500A1 (en) 1990-07-31 1992-02-20 Teikoku Hormone Mfg. Co., Ltd. 2-phenylindole derivative
WO1998022457A1 (en) 1996-11-19 1998-05-28 Amgen Inc. Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
US20040180946A1 (en) 2002-09-12 2004-09-16 Sircar Jagadish C. Phenyl-indole compounds for modulating IgE and inhibiting cellular proliferation
WO2005005414A2 (en) 2003-07-08 2005-01-20 Pharmacia Italia S.P.A. Pyrazolyl-indole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
WO2007057329A1 (en) 2005-11-18 2007-05-24 F. Hoffmann-La Roche Ag Azaindole-2-carboxamide derivatives
WO2011097079A1 (en) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Apoptosis signal-regulating kinase 1 inhibitors
WO2011117264A1 (en) 2010-03-26 2011-09-29 F. Hoffmann-La Roche Ag N-(imidazopyrimidin-7-yl)-heteroarylamide derivatives and their use as pde10a inhibitors
WO2011133637A2 (en) 2010-04-21 2011-10-27 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
WO2012123745A1 (en) 2011-03-14 2012-09-20 Cancer Research Technology Limited Pyrrolopyridineamino derivatives as mps1 inhibitors
US20120295904A1 (en) 2009-10-13 2012-11-22 Ligand Pharmaceuticals Inc. Hematopoietic growth factor mimetic small molecule compounds and their uses
US20130338201A1 (en) 2009-11-02 2013-12-19 Ahr Pharmaceuticals, Inc. Method of Cancer Treatment with 2-(1H-Indole-3-Carbonyl)-Thiazole-4-Carboxylic Acid Methyl Ester
WO2014060328A1 (en) 2012-10-17 2014-04-24 F. Hoffmann-La Roche Ag 6-aminoindole derivatives as trp channel antagonists
WO2014100620A2 (en) 2012-12-21 2014-06-26 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9102672B2 (en) * 2006-11-03 2015-08-11 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US20160175278A1 (en) 2010-07-27 2016-06-23 Trustees Of Boston University ARYL HYDROCARBON RECEPTOR (AhR) MODIFIERS AS NOVEL CANCER THERAPEUTICS
WO2018141857A1 (en) 2017-02-01 2018-08-09 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (ahr) modulator compounds
WO2018141855A1 (en) 2017-02-01 2018-08-09 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (ahr) modulator compounds
WO2018153893A1 (en) 2017-02-21 2018-08-30 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (ahr) modulator compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8604067B2 (en) 2009-11-02 2013-12-10 Ahr Pharmaceuticals, Inc. ITE for cancer intervention and eradication

Patent Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992002500A1 (en) 1990-07-31 1992-02-20 Teikoku Hormone Mfg. Co., Ltd. 2-phenylindole derivative
WO1998022457A1 (en) 1996-11-19 1998-05-28 Amgen Inc. Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
US20040180946A1 (en) 2002-09-12 2004-09-16 Sircar Jagadish C. Phenyl-indole compounds for modulating IgE and inhibiting cellular proliferation
WO2005005414A2 (en) 2003-07-08 2005-01-20 Pharmacia Italia S.P.A. Pyrazolyl-indole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
WO2007057329A1 (en) 2005-11-18 2007-05-24 F. Hoffmann-La Roche Ag Azaindole-2-carboxamide derivatives
US9102672B2 (en) * 2006-11-03 2015-08-11 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US20120295904A1 (en) 2009-10-13 2012-11-22 Ligand Pharmaceuticals Inc. Hematopoietic growth factor mimetic small molecule compounds and their uses
US20130338201A1 (en) 2009-11-02 2013-12-19 Ahr Pharmaceuticals, Inc. Method of Cancer Treatment with 2-(1H-Indole-3-Carbonyl)-Thiazole-4-Carboxylic Acid Methyl Ester
WO2011097079A1 (en) 2010-02-03 2011-08-11 Takeda Pharmaceutical Company Limited Apoptosis signal-regulating kinase 1 inhibitors
WO2011117264A1 (en) 2010-03-26 2011-09-29 F. Hoffmann-La Roche Ag N-(imidazopyrimidin-7-yl)-heteroarylamide derivatives and their use as pde10a inhibitors
WO2011133637A2 (en) 2010-04-21 2011-10-27 Plexxikon, Inc. Compounds and methods for kinase modulation, and indications therefor
US8901118B2 (en) 2010-04-21 2014-12-02 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US20160175278A1 (en) 2010-07-27 2016-06-23 Trustees Of Boston University ARYL HYDROCARBON RECEPTOR (AhR) MODIFIERS AS NOVEL CANCER THERAPEUTICS
WO2012123745A1 (en) 2011-03-14 2012-09-20 Cancer Research Technology Limited Pyrrolopyridineamino derivatives as mps1 inhibitors
WO2014060328A1 (en) 2012-10-17 2014-04-24 F. Hoffmann-La Roche Ag 6-aminoindole derivatives as trp channel antagonists
WO2014100620A2 (en) 2012-12-21 2014-06-26 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9676748B2 (en) 2012-12-21 2017-06-13 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2018141857A1 (en) 2017-02-01 2018-08-09 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (ahr) modulator compounds
WO2018141855A1 (en) 2017-02-01 2018-08-09 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (ahr) modulator compounds
WO2018153893A1 (en) 2017-02-21 2018-08-30 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (ahr) modulator compounds
US20200031805A1 (en) 2017-02-21 2020-01-30 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (ahr) modulator compounds

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
Bessede et al., "Aryl hydrocarbon receptor control of a disease tolerance defence pathway," Nature 511: 184-190, 2014 (19 pages).
Foster, "Deuterium isotope effects in studies of drug metabolism," Trends in Pharmacological Sciences 5: 524-527, 1984 (5 pages).
Hanan et al., "Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation," J. Med. Chem. 57: 10176-10191, 2014.
International Search Report, dated Mar. 12, 2018, for International Application No. PCT/EP2018/052542, 4 pages.
International Search Report, dated Mar. 29, 2018, for International Application No. PCT/EP2018/052538, 5 pages.
International Search Report, dated May 3, 2018, for International Application No. PCT/EP2018/054234, 5 pages.
Kerkvliet, Biochem Pharm, vol. 77, 2009, 746-760. (Year: 2009). *
Koliopanos et al., "Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer," Oncogene 21: 6059-6070, 2002.
Li et al., "Expression of aryl hydrocarbon receptor in relation to p53 status and clinicopathological parameters in breast cancer," Int. J. Clin. Exp. Pathol. 7(11): 7931-7937, 2014.
Li et al., "LEADOPT: An automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors," European Journal of Medicinal Chemistry 93: 523-538, 2015.
Monteleone, Gastroenterology, vol. 28 (4), 310-313, 2012. (Year: 2012). *
Murray et al., "AH Receptor Ligands in Cancer: Friend and Foe," Nat. Rev. Cancer 14(12): 801-814, 2014.
Naud et al., "Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)," J. Med. Chem. 56: 10045-10065, 2013.
Official Action from Chile Ministerio de Economia dated Jul. 13, 2020, for Application No. 201902108 filed Feb. 1, 2018, 12 pages.
Official Action from European Patent Office re extended European search report, dated Mar. 22, 2017, for Patent Application No. 17000157.2, 10 pages.
Official Action from European Patent Office re extended European search report, dated Mar. 23, 2017, for Patent Application No. 17000158.0, 4 pages.
Official Action from European Patent Office re extended European search report, dated Mar. 30, 2017, for Patent Application No. 17000276.0, 5 pages.
Official Action from Intellectual Property India dated Mar. 17, 2020, for Application No. 201917029340, 6 pages.
Official Action from Intellectual Property India dated Sep. 11, 2020, for Application No. 201917029343, 5 pages.
Official Action from Japan Patent Office dated Sep. 15, 2020, for Application No. 2019-561370, 3 pages (translation).
Richmond et al., "The Aryl Hydrocarbon Receptor Is Constitutively Active in Advanced Prostate Cancer Cells," PLOS One 9(4): e95058, 2014 (11 pages).
Romani et al., "Microbiota control of a tryptophan-AhR pathway in disease tolerance to fungi," Eur. J. Immunol. 44: 3192-3200, 2014.
Safe et al., "Role of the Aryl Hydrocarbon Receptor in Carcinogenesis and Potential as a Drug Target," Toxicological Sciences 135(1): 1-16, 2013.
U.S. Appl. No. 16/479,847, filed Jul. 22, 2019, Steeneck et al.
U.S. Appl. No. 16/483,981, filed Aug. 6, 2019, Deuschle et al.
Vezina, Biochem Pharm, vol. 77, 566-576, 2009. (Year: 2009). *
Zelante et al., "Tryptophan Catabolites from Microbiota Engage Aryl Hydrocarbon Receptor and Balance Mucosal Reactivity via Interleukin-22," Immunity 39: 372-385, 2013.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11376241B2 (en) * 2017-02-01 2022-07-05 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (AhR) modulator compounds

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